Pharmaceutical Organic Chemistry II (PC 204) Lecture Notes PDF

Pharmaceutical Organic chemistry II (PC 204) DR. MENNA ISMAIL Doctor of Pharmaceutical Chemistry Faculty of Pharmacy Egyptian Chinese University Email : [email protected] Office Hours: Monday 12:30- 2:3...

Pharmaceutical Organic chemistry II (PC 204) DR. MENNA ISMAIL Doctor of Pharmaceutical Chemistry Faculty of Pharmacy Egyptian Chinese University Email : [email protected] Office Hours: Monday 12:30- 2:30 1 Course Weight Periodical exam 20 Marks Practical examination 40 Marks Final Examination 75 Marks Oral Examination 15 Marks Total 150 Marks  Course Specifications 1. Overall Aims of the Course: The course aims to cover different classes of aliphatic and aromatic organic compounds regarding their nomenclature, physical properties, methods of preparation and different reactions as well as basic concepts of stereochemistry. The aim of the course is to ensure that students can effectively demonstrate knowledge of basic concepts of organic chemistry and carry out simple organic experiments under supervision the supervision of their instructors, and to ensure that students have achieved the competencies of integration of the knowledge obtained from studying this course with the coming advanced courses. 3 1.1.1.1. Recognize the concepts of aliphatic and aromatic organic chemistry and their reactions. 1.1.1.2. Outline the basic concepts of stereochemistry including isomerism, spatial and three-dimensional arrangement of organic compounds. 1.1.2.1. Define basic and important scientific terms related to organic and stereochemistry. 1.1.3.1. Outline the basic concepts of different functional group in the preparation of various organic compounds using the appropriate synthetic route. 4 2.2.1.1. Select the appropriate method of identification of organic compounds from both its physical properties and chemical reactions (reactions of functional groups) adopting the Good Lab. Practice (GLP) rules and regulations. 2.2.1.2. Construct 3-D models of some organic compounds helping the identification of isomerism in organic compounds. 2.2.1.3. Solve stereochemical problems to differentiate between different isomers. 2.3.1.1. Performing the ecofriendly techniques and MSDS importance in dealing with labs. 5 4.1.1.1. Appraise effective time management skills 4.1.2.1 Work effectively as part of a team and individually 4.2.1.1. Enhance communication using proper spoken and written language 6  Topics Aryl halides (Nomenclature, physical properties, preparation and Nucleophilic substitution 1 reactions; SN1 – SN2 mechanisms) 2 Alcohols (Nomenclature, physical properties, preparation, reactions of alcohols,) Phenols (Nomenclature, physical properties, acidity of phenols, synthesis and reactions of 3 Phenols) 4 Aldehydes and Ketones (Nomenclature, physical properties, synthesis and reactivity) 5 Carboxylic acids and their derivatives (Nomenclature, physical properties, synthesis and reactivity) 6 Nitrogenous compounds (Nomenclature, physical properties, synthesis and reactivity) Introduction to stereochemistry, types of isomers, Types of constitutional isomers Types of 7 Stereoisomers: Conformational and Geormetric Isomers) 8 Stereoisomers: Chiral molecules and optical activity, Representation of Stereoisomers. Stereochemistry: Enantiomers & diastereomers, Relative and absolute configuration, Racemic 9 forms and racemization 10 Revision 7  Lecture 1 Alkyl halides (Haloalkanes) R-X Classification Nomenclature Physical properties Synthesis Reactions 8 Classification of alkyl halides (According to the nature of the carbon bonded to the halogen) Alkyl Halides 1○ halide 2○ halide 3○ halide Compounds of Compounds of Compounds of the the type RCH2-X, the type R 2CH-X type R 3C-X Ethyl bromide Isopropyl bromide Tert-butyl bromide 9  I. Nomenclature 1] Common or "trivial" names: Examples: Alkyl + Halide Pentyl Chloride 10 2] IUPAC Nomenclature: (Substitutive Nomenclature) Halogens (X) are considered substituents not functional group Step (1)-Find the longest chain and name it as the parent (if double bond or triple bond is present the parent must contain it). Step (2)-Number the carbons of the parent chain beginning at the end nearer to the first substituent whether alkyl or halogen. 11 Step (3): If the parent can be numbered from either end by step 2 begin from the end nearer the substituent that has alphabetical precedence. 12  II. Physical properties 1] Boiling Points 1] Haloalkanes have considerably higher boiling points than alkanes of the same number of carbons because of their greater molecular weights. 2] For a given alkyl group, the boiling point increases with increasing atomic weight of the halogen, so that fluoride is the lowest boiling and an iodide the highest boiling. (RI > RBr > RCl > RF) 2] Solubility RX insoluble in water, soluble in nonpolar solvent. 13  III. Synthesis of Alkyl Halides 1] Free-radical halogenation of alkanes. 2] Hydrohalogenation of alkenes. 3] From alcohols: A. Reaction of Alcohols With HX B. Reaction With Thionyl Chloride, SOCl2 or With PBr3 14 1- Free-radical halogenation of alkanes (Free radical substitution reaction( Under the influence of UV light, or at 250- 400 °C, Chlorine and bromine converts alkanes into chloroalkanes or bromoalkanes. Br2 is less reactive but more selective than chlorine so reacts with 3○ hydrogen. while Cl2 is more reactive than Br2 and reacts with 1○, 2○ and 3○ hydrogens. 15 2- Hydrohalogenation of alkenes: Electrophilic Addition Reactions, (Markovnikov’s Rule, rich gets richer, Hydrogen adds to carbon with more number of hydrogens) Order: HI > HBr > HCl > HF (dry gases). What is the disadvantage????? Discussed before (see alkenes) 16 Examples: X N.B. (Rearrangement) 17 3- From Alcohols: a) Reaction of alcohols with HX: Order: HI > HBr > HCl > HF Acid catalyzed = protonation The reaction mechanism depends on the structure of the alcohol, 1o alcohol reacts via SN2 mechanism since these have highly unfavorable carbocations while 3o reacts via SN1. Mechanism The reaction starts by protonation of OH. Convert from (Bad leaving group) to H2O (Good leaving group) SN2 (Back side attack) Carbocation intermediate SN1 (2 steps) 19  Examples: In case of 2o alcohols and 1o alcohol with β-branching rearrangement may occur to form more stable carbocation. Lucas test: Test for differentiation between 1°, 2° or 3° alcohol which is based upon the difference in reactivity of the three classes towards HX. Alcohols are soluble in Lucas reagent (mixture of conc. HCl & ZnCl2). ZnCl2 (Lewis) acid can form complex with unshared electron pair of oxygen that provides better leaving group than H2O. The formed RCl is water insoluble & its formation is indicated with appearance of cloudiness. 3o alcohols react immediately. 2o alcohols react within 5 minutes. 1o alcohols does not react at RT. 21 b) By using SOCl2 or PBr3: These reactions do not proceed via the formation of carbocation; hence NO REARRANGEMENT occurs. PBr3 is prepared in situ by reacting elemental phosphorous with bromine liquid. 22  IV. Reactions of Alkyl Halides Important Note: Alkyl halides, have their halide (electronegative atom) bonded to an sp3 hybridized carbon so can undergo substitution and/or elimination reactions. Alkenyl halides and aryl halides (sp2) are inactive under the same conditions. 23 Polarity of C–X bond: The carbon-halogen bond of alkyl halides is polarized (due to difference in electronegativity). A halogen is more electronegative than carbon so it has a partial negative charge and the carbon to which it is bonded has a partial positive charge. X = F, CI, Br, I 24  Reactions of Alkyl Halides: 1. Alkyl halides undergo either Nucleophilic Substitution reactions (SN1 & SN2) and / or Elimination reactions (loss of HX to give alkenes). 2. Alkyl halides also react with Li or Mg to give organometallic compounds e.g. Grignard reagent, organolithium, copper and cadmium compounds. 25  1- Nucleophilic Aliphatic Substitution Reaction: A: SN2 Mechanism (Nucleophilic Substitution Bimolecular): SN2 is a one step reaction where a nucleophile reacts directly with an organic substrate such as an alkyl halide. Bimolecular mechanism means that the rate limiting step of the reaction (formation of the T.S) depends on the concentration of both reactants (RX & Nü), (second order reaction). e.g. N.B. The order of reactivity of RX towards SN2: RI > RBr > RCl > RF as I forms the weakest bond with carbon and the best leaving group. 26  Mechanism of SN2 reaction: 1- Hydroxide ion (Nü) attacks the back side of the electrophilic carbon atom, donating a pair of electrons to form a new bond with formation of a transition state (T.S). 2- C-X bond begins to break as the C-Nu bond begins to form. 3- -X ion is the leaving group; it leaves with the pair of electrons that once bonded to the carbon atom. 27 Factors affecting the rate of SN2 reaction:- a. Structure of RX (alkyl halide): SN2 is affected by steric hindrance because of the backside attack of Nü. The order of reactivity of R towards SN2: CH3 > 10 > 20 > 30 As 30 RX are more hindered than 20 RX which are more hindered than 10. 28  b. Nucleophilicity of the Nü: SN2 reactions depend on the effectiveness of the nucleophile. (i) For a given element, negatively charged species are more nucleophilic (and basic) than equivalent neutral species. e.g. OH- > H2O, RO- > ROH, NH2- > NH3 (ii) For a given period of the periodic table, nucleophilicity (and basicity) decreases on moving from left to right. (iii) For a given group of the periodic table, nucleophilicity increases from top to bottom due to the increase in size and polarizability. e.g. I- > Br- > Cl- > F- 29 Functional Group Transformations Using SN2 Reactions: SN2 reactions are highly useful in organic synthesis because they enable us to convert one functional group into another. (i.e. prepare other classes of organic compounds). - OH R OH (Alcohol) - R`O R OR` (Ether) - CN R C N (Nitrile) - SH R SH - R-X C CR` R C C R` (Alkyne) Alkyl O (R= Me, 1° or 2°) halide) R`COO - R OCR` (Ester) - I R I - N3 R N3 (Azide) NH3 RNH2 (Amine) 30 B: SN1 mechanism (Nucleophilic Substitution Unimolecular): SN1 is a two step reaction in which the rate-determining step consists of the ionization of the alkyl halide to give carbocation intermediate. Unimolecular mechanism means the reaction depends only on the concentration of the alkyl halide and independent on the concentration of the nucleophile, (first order reaction). e.g. H2O weak Nu Substitution (SN1) occurs 31 Mechanism of SN1 reaction: Step 1: Ionization of C-X bond to form a carbocation intermediate. CH3 CH3 slow, rate determining step Br - H3C C + C Br H3C CH3 H3C carbocation intermediate (Trigonal, planar) Step 2: Reaction of the carbocation with the nucleophile. CH3 CH3 CH3.. + + + CH3OH CH3 C-O-CH3 + CH3-O-C CH3 C.. H3C CH3 CH3 CH3 H H -H+ CH3 CH3 N.B. If the solvent acts as nucleophile the reaction in this case is called solvolysis. CH3 C-O-CH3 + CH3-O-C CH3 CH3 CH3 32 Factors affecting the rate of SN1 reaction:- a. Structure of RX (alkyl halide): SN1 is affected by the stability of carbocation intermediate. (R+) The order of reactivity of RX towards SN1 reactions is: 3o > 2o > 1o > CH3 alkyl halides. b. Nature of X: RI > RBr > R-Cl > R-F The same as SN2 reactions. 33  *Competition between nucleophilic substitution & Elimination: In some cases substitution occur and in others elimination. What factors favor substitution or elimination? 1) Type of base: Strong base (e.g. sodium amide) favor elimination. N.B: The greater the size of base favor elimination e.g. K tert.butoxide as the bulky group cause steric hinderance of substitution. 2) Temperature: High temperature favors elimination. Examples: Alcoholic KOH strong Nu Elimination occurs 34  Types of Nucleophilic Substitution Reactions SN2 SN1 One step: Backside attack of new Nu and Two steps :1) Present Nu leaves departure of present Nu at same time. forming carbocation. 2) Attack of new Nu. Occurs in 1° alkyl halides (No bulkiness) Occurs in 3° alkyl halides (bulkiness prevents backside attack) Nucleophile used may be: Nucleophile used : Weak Nu only. (a)Weak Nu (have unshared es pair In case of strong and basic (b)Strong Nu (have –ve charge): Nu, elimination occurs NOT substitution  Organometallic Compounds Compounds have C-M bond. C-M ranging from ionic to primarily covalent bonds according to the difference in EN. δ δ The reactivity of organometallic compounds increases with the percent ionic character of the C-M bond. Alkyl sodium and alkyl potassium compounds are highly reactive and are among the most powerful bases. Organocadmium and organocopper compounds are much less reactive. 36  Organometallic Compounds Preparation: R may be (1o , 2o ,3o), cycloalkyl. Order of reactivity of RX is RI > RBr > RCl > RF Solvent must be anhydrous (usually ether or THF). What is the importance of organometallic compounds????? 37  Organometallic Compounds Reactions: R acts as nucleophile (R has a partial negative charge) as it loses the MgX and form a carbanion. 1- Grignard reagents and organolithium compounds are very strong bases. They react with compounds that have relative acidic hydrogen e.g. water, alcohols, amines, carboxylic acids and terminal alkynes to yield hydrocarbons and metal salts. − + R MgX + H OH R H + XMgOH − + R Li + R`C CH R`C C Li + R H 2- Grignard reagents are not only strong bases, but they are also powerful nucleophiles. In particular, the reaction of organolithium compounds and Grignard reagents with carbonyl compounds produce alcohols. (Later in alcohols) H H H3O+ RMgX + O R-C-OMgX R-CH2OH (1oalcohol) H H 38  Unsaturated Halogen Compounds: Haloalkenes These compounds may be sharply divided into 2 classes: Vinylic Halides (CH2=CH-X) Allylic Halides (CH2=CH-CH2-X) 1) Vinylic Halides: These compounds are generally unreactive in SN1 or SN2 reactions. Unreactive towards SN1 reactions because the vinylic cations are relatively unstable and not readily formed. SN1 H2C CH X H2C CH + A vinyl carbocation (Highly unstable) X Unreactive towards SN2 reactions because: Nu a) electrons of the double bond repel approach of the Nü. CH2 CH X b) C-X bond in vinyl halides is stronger than that of the alkyl halides which could be explained by resonance, C-X bond has degree of double bond character. H2C CH X CH2 CH X 39 2) Allylic Halides: Allylic halides are more reactive than vinyl halides & alkyl halides towards both SN1 and SN2, Why? Reactive towards SN1 reactions due resonance stabilization of the formed allylic carbocation. Allyl carbocation (Highly stable by resonance) Reactive towards SN2 reactions because it is primary alkenyl halide with no steric hindrance effect. Nu H2 C CH CH2 X 40  Summary of alkyl halide Synthesis of alkyl halide 1] Free-radical halogenation of alkanes. (Br for 3o alkane, Cl f or all) , heat 2] Hydrohalogenation of alkenes.(HI>HBr>HCl>HF), Rearrangement 3] From alcohols: A. Reaction of Alcohols With HX (3o alc > 2o > 1o , (HI>HBr>HCl>HF), B. Reaction With Thionyl Chloride, SOCl2 or With PBr3 no rearrang. Reactions of alkyl halide 1] SN2 (1o alkyl halide) 2] SN1 (3o alkyl halide) (in case of strong Basic Nu elimination occurs) 3] E2 with strong basic or bulky nucleophile or high temperature 4] Synthesis of organometallic compounds 41  Exercise???? 1- Complete the following equations: 42 43 44